1. Field of the Invention
The present invention relates to antibodies and/or fragments thereof having specificity for MN protein. The invention further relates to antibody and/or immunoconjugate compositions and their use in treating, preventing, and/or diagnosing MN-related disorders, e.g. cancer.
2. Background
The occurrence of cancer is most commonly associated with aging whereby 65% of all new cases of cancer are recorded for patients aged 65 and over. Cancer is the second leading cause of death in the United States, exceeded only by heart disease. Indeed, the American Cancer Society has estimated that 1 in 4 people will die from cancer in the U.S., assuming current mortality rates remain static. In the U.S. alone, 1,399,790 new cases and 564,830 deaths from cancer are expected in 2006. The majority of these new cases are expected to be cancers of the colon (106,680), lung (172,570) and breast (214,640). Moreover, both the incidence and prevalence of cancer is predicted to increase approximately 15% over the next ten years, reflecting an average growth rate of 1.4% (American Cancer Society, 2006).
One recently identified tumor associated antigen, MN, a cell surface protein, has been found to be expressed in a number of clinical carcinomas. For example, MN has been found to be ectopically expressed in 100% of renal cell carcinomas (Liao, S Y, Cancer Res., 1997, 57:2827-2831), 100% of carcinomas of the esophagus (Turner J R, Hum. Pathol., 199, 28:740-744), greater than 90% of cervical carcinomas (Liao, S Y, Cancer Res., 1997, 57:2827-2831), 76% of malignant colon carcinomas (Saarnio, J. et al., Am. J. Path., 1997, 153:279-285), 80% of non-small cell lung carcinomas (Vermylen P. et al., Eur. Respir. J., 1999, 14:806-811), and in 48% of breast cancers (Chia S K et al., J. Clin. Oncol., 2001, 19:3660-3668). Like other tumor associated antigens, the MN protein is also present on cells of a limited number of normal tissues, including, for example, stomach, bile duct mucosa and the highly proliferate normal cells located in the small intestine (Saarnio J. et al., J. Histochem. Cytochem, 1998, 46:497-504).
Human MN cDNA has been cloned and sequenced (Pastorek, et al., Oncogene, 1994, 9:2877-2888). The predicted protein consists of a signal peptide, a proteoglycan-related sequence, a carbonic anhydrase domain (carbonic anhydrase 1× or CA IX), a transmembrane segment, and a short intracellular tail. The carbonic anhydrase IX domain catalyzes the reversible hydration of carbon dioxide to carbonic acid. This activity may have a role in regulating the local acidification of the extracellular portion of the tumor environments, which may consequently lead to the activation of proteases and finally, metastasis.
The regulation of MN expression has also been investigated. In one aspect, for example, MN expression is up-regulated by hypoxia. The transcriptional complex known as hypoxia-inducible factor-1 (HIF-1) is a regulator of MN expression. Accordingly, MN is known as a HIF-1 responsive gene which has implications in the understanding of tumor response to hypoxia (Wykoff C C et al., Cancer Res., 2000, 60:7075-7083). Furthermore, MN expression correlates with tumor hypoxia levels and is a prognostic indicator of overall survival and metastasis-free survival in cervical cancer (Loncaster, J A et al., Cancer Res., 2000, 60:7075-7083). MN expression also correlates with a high mean vessel density, advanced cancer stage, degree of necrosis in head and neck carcinoma (Beasley N J P et al., Cancer Res., 2001, 61:5262-5267), poor survival in nasopharyngeal carcinoma (Hui E P et al., Clin. Cancer Res., 2002, 8:2595-2604), tumor necrosis, higher grade, negative estrogen receptor status, higher relapse rate, and poor survival for invasive breast carcinoma (Chia S K et al., J. Clin. Oncol., 2001, 19:3660-3668). Therefore expression of MN antigen is correlates with poor survival prognosis, and cancers of higher grade.
New and improved therapies for these aggressive cancers, in particular, those that target MN expression, are highly desirable and would represent an advancement in the art. As such, the present invention discloses new antibody compositions and immunoconjugates thereof that are useful in the treatment, prevention and/or diagnosis of MN-related cancers.